Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-11-06
1997-11-18
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540300, C07D51304, C07D50708
Patent
active
056889429
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process for preparing 2-isocephem derivatives or 2-oxaisocephem derivatives. More particularly, the invention relates to a process for preparing 3-halomethyl-2-isocephem derivatives or 3-halomethyl-2-oxaisocephem derivatives useful as intermediates for introducing various functional groups into the 3-position methyl group of 2-isocephem derivatives or 2-oxaisocephem derivatives which are cephalosporin antibiotics of the unnatural type.
BACKGROUND ART
The antibacterial activities of 2-isocephem derivatives and 2-oxaisocephem 1190(1988)!. Especially, 3-halomethyl derivatives thereof are important intermediates for preparing 3-alkenyl-2-isocephem derivatives and 2-oxaisocephem derivatives (JP-A-253008/1988, JP-A-31285/1991) which are nonnatural-type cephalosporin antibiotics, whereas reports have merely been made on several production examples of such derivatives up to date.
However, the production processes reported each have some problems, so that it has been desired to develop new production processes. For example, the processes have the following problems.
(1) The process disclosed in JP-B-32317/1986 and Can. J. Chem., Vol. 56, 1335(1978) comprises treating a 2-azetidinyl-3,4-dihalogeno-2-butenoic acid compound with a base derived from carboxylic acid having pKa of 3.5 to 5.5 to obtain 3-acyloxymethyl-2-oxaisocephem derivative by ring closure, hydrolyzing the derivative to prepare a 3-hydroxymethyl-2-oxaisocephem derivative and treating the resulting derivative with a phosphorus halide to prepare a 3-halomethyl-2-oxaisocephem derivative as represented by the following reaction formula-1. The disclosed process results in a low yield, requires many reaction steps and uses a phosphorus compound having environmental problems such as a stringent waste water regulation. ##STR4##
(2) The process disclosed in J-A-31285/1991 and J. Mad. Chem., 31, 1190(1988) wherein an azetidinone derivative having hydroxymethyl at the 4-position is tert-butyldimethylsilylated and then enolized with lithiumbis-trimethylsilylacetamide, followed by a reaction with halogenated acetyl chloride and then by MITSUNOBU reaction (dehydration condensation reaction using an azodicarboxylic acid ester and triphenylphosphine) for ring closure uses expensive reagents, requires a cryogenic temperature, includes many steps and is therefore industrially infeasible. ##STR5##
Thus, processes still remain to be developed which are free of all the problems about economy, yield, safety, work environment, etc.
An object of the present invention is to provide a novel cephem derivative production process for preparing a 3-halomethyl-2-isocephem derivative or 3-halomethyl-2-oxaisocephem derivative by a single step from a 2-azetidinyl-3,4-dihalogeno-2-butenoic acid compound represented by the general formula (1) and easily available, effectively utilizing the halogen atom at the 4-position.
DISCLOSURE OF THE INVENTION
The present invention provides a process for preparing a 2-isocephem derivative characterized in that a thioacetic acid derivative which itself is basic or a mixture of a base and a thioacetic acid derivative is caused to act on a 2-azetidinyl-3,4-dihalogeno-2-butenoic acid compound represented by the general formula (1) in a water-containing organic solvent to obtain a 3-halomethyl-2-isocephem derivative represented by-the general formula (2), and a process for preparing a 2-oxaisocephem derivative characterized in that a base is caused to act on a 2-azetidinyl-3,4-dihalogeno-2-butenoic acid compound represented by the general formula (1) in a water-containing organic solvent to obtain a 3-halomethyl-2-oxaisocephem derivative represented by the general formula (3) ##STR6## wherein R.sup.1 is a hydrogen atom, amino or protected amino, R.sup.2 is a hydrogen atom or lower alkoxyl, R.sup.1 and R.sup.2, when taken together, form a cyclic amino protecting group, R.sup.3 is a hydrogen atom or carboxylic acid protecting group, W is a leaving group, and X and Y are the same or different and are
REFERENCES:
Hakimelahi, G.H. et al. Helv. Chim. Acta, vol. 75, pp. 1840-1847 (1992).
Sasaoka Michio
Suh Delsoo
Suzuki Daisuke
Tokumaru Yoshihisa
Otsuka Kagaku Kabushiki Kaisha
Shah Mukund J.
Wong King Lit
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